FDA Approves Frontline Pembrolizumab/Chemotherapy in Advanced Mesothelioma

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• The FDA approved the frontline combination of pembrolizumab (Keytruda) and chemotherapy in patients with unresectable advanced or metastatic malignant pleural mesothelioma.
• This approval is supported by findings from the 2/3 KEYNOTE-483 trial (NCT02784171).
• Here, pembrolizumab plus chemotherapy in the firstline led to a statistically significant and clinically meaningful improvement in overall survival (OS) vs chemotherapy alone.

The FDA has granted approval to the first-line treatment of pembrolizumab combined with chemotherapy in patients with unresectable advanced or metastatic malignant pleural mesothelioma.¹

Data from the randomized, open-label, phase 2/3 KEYNOTE-483 trial (NCT02784171) support this approval.² According to findings presented at the 2023 American Society of Clinical Oncology Annual Meeting, the combination of pembrolizumab with chemotherapy led to a statistically significant improvement in OS, reducing the risk of death by 21% (HR, 0.79; 95% CI, 0.64-0.98; 2-sided P =.0324). The median OS with the combination was 17.3 months (95% CI, 14.4-21.3) vs 16.1 months (95% CI, 13.1-18.2) with chemotherapy alone.

A significant improvement in progression-free survival (PFS) was also observed with the combination. The PFS was 7.13 months (HR, 0.80; 95%CI, 0.65-0.99; 2-sided P =.0372) with the combination vs 7.16 months with chemotherapy, and at 12 months, the estimated PFS rates across arms were 26% and 17%, respectively. The overall response rate (ORR) was also significantly higher for the pembrolizumab combination at 62% vs 38% with chemotherapy alone (P <.0001).

For safety, the safety profile of pembrolizumab plus chemotherapy in this study was consistent with what has been previously reported.

Those with measurable disease; an ECOG performance status of 0 or 1; and adequate hematologic, liver, and renal function and those who had no contraindications to standard chemotherapy were eligible for enrollment in the study.³ Patients must have also been eligible to receive standard chemotherapy with pemetrexed and cisplatin and must have been incurable with use of standard therapies to be included in the study. Patients were permitted to have had prior radiation at least 28 days prior to registration; however, radiation to the thorax was not allowed unless clear disease progression was seen. Further, patients were permitted to have undergone previous major surgery at least 28 days prior to registration.

There were 440 patients enrolled during the phase 3 portion and randomized to receive 200 mg of pembrolizumab given intravenously every 3 weeks for up to 35 cycles in combination with 500 mg/m2 of pemetrexed every 3 weeks for 6 cycles and 75 mg/m2 of cisplatin every 3 weeks for 6 cycles. Patients also could have been given pemetrexed plus cisplatin alone. Cisplatin could be substituted with carboplatin at an area under the curve of 5 or 6 every 3 weeks for 6 cycles in either arm.

REFERENCES:
1. FDA approves pembrolizumab with chemotherapy for unresectable advanced or metastatic malignant pleural mesothelioma. News release. FDA. September 17, 2024. Accessed September 18, 2024. https://tinyurl.com/mwb4h6rj

2. Chu QS, Piccirillo MC, Greillier L, et al. IND227 phase III (P3) study of cisplatin/pemetrexed (CP) with or without pembrolizumab (pembro) in patients (pts) with malignant pleural mesothelioma (PM): a CCTG, NCIN, and IFCT trial. J Clin Oncol. 2023;41(suppl 17):LBA8505. doi:10.1200/JCO.2023.41.17_suppl.LBA8505

3. Pembrolizumab in patients with advanced malignant pleural mesothelioma. ClinicalTrials.gov. Updated January 16, 2024. Accessed August 23, 2024. https://clinicaltrials.gov/